TW200836742A - Benzoquinazoline derivatives - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or prodrug ester thereof: wherein R is as defined in the specification.

Description

200836742 IX. Description of invention: [Technical field to which the invention belongs]

This invention relates to bicyclic compounds, especially to the 2-benzo quinazoline derivatives, and to their pharmaceutical use. Soil /T [Invention content]

Accordingly, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof: X

(I) wherein -R represents a group having 2 fused ring-fluorene-fluorenes, wherein hydrazine is optionally substituted with a heteroaryl or aryl group and B is optionally one or more selected from the group consisting of hydrazine and s. a saturated or unsaturated 4, 5, 6 or 7 membered ring of a hetero atom; an optional substituent on R is one or more groups independently selected from the group consisting of the following groups: pendant oxy group, cyano group , halo or other optionally substituted alkyl, c2-c6 alkenyl, CrCs alkoxy and amine; other optional substituents selected from cyano, halo, C1_C6 alkyl, alkenyl, 匚 匕Alkoxy and amine groups. The following meanings are independent, common or in any combination or sub-combination. 128031.doc 200836742 Preferably: (i) A is a phenyl group; (ii) octa is phenyl and B is at the 3' position of the phenyl group and 4 (i) B is a 5-membered ring; (iv) B is a 6-membered ring; (v) 6 is saturated (preferably highly saturated); (vi) B is unsaturated; Vii) B contains 1 heteroatom; (viii) B contains 2 heteroatoms; (ix) B contains oxygen; (X) B contains 2 oxygens, each of which is directly bonded to the heteroaryl or aryl group Or (xi) B is saturated and contains no heteroatoms; or (xii) B is saturated and contains 1 heteroatom. For the avoidance of doubt, the terms listed above and below are to be understood as having the following meanings throughout the specification and the scope of the patent application. The term π low carbon π means an organic group or compound means a compound or a group thereof A bond or an unbranched 'which has at most 7 and includes 7 1 atoms. The lower carbon group may be branched, unbranched or cyclic and contains from 1 to 7 carbon atoms' preferably from 1 to 4 carbon atoms. The low charcoal burnt group means, for example, meflate, propyl, butyl, isopropyl, isobutyl, tert-butyl or 2,2-dimethylpropyl. The lower alkoxy group may be branched or unbranched and contains from 1 to 7 carbon atoms, 128031.doc 200836742 preferably from 1 to 6 carbon atoms. The lower alkoxy group means, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, an isobutoxy group or a tert-butoxy group. Low Weioxy includes cyclodecyloxy and ring-based (4), (iv) depends on w-cut = 2 to 7 carbon atoms, preferably! Up to 4 carbon materials and containing at least one carbon-carbon double bond. The lower alkene, lower alkenyl or lower alkoxy group means, for example, a vinyl group, a propyl group + a dilute group, a dipropyl group, a butythyl group, an isopropyl group or an isobutyl group, and a base equivalent. Low carbon fast or fast radicals are branched or unbranched and contain 2 to 7 carbon atoms, preferably: up to 4 carbon atoms, and contain at least one carbon-carbon bond. A low carbon block or a low stone block base or a low carbon dilute base group means, for example, an ethyl group or a propyl group. In the two applications, 'oxygen-containing substituents, such as alkoxy, diloxy, block =, fluorenyl, etc., cover their sulfur-containing homologues, such as sulphur-burning, alkyl-thionite, sulphur-based, and women. Base thione, sulfur block, thiol group, stone wind, sapite and the like. A dentate group or a phenolic group * a chloro group, a gas group 1 group or a moth group. The aryl group means a carbocyclic aryl group or a diaryl group. The base is an aromatic ring smoke containing 6 to 18 ring atoms. It may be a mono-, di- or tri-cyclic ring such as a hydrazine, a butyl group, a basic group, or a phenyl group which is substituted, disubstituted or trisubstituted with 1, 2 or 3 substituents. "Aryl or heteroaryl is one of the second ring atoms containing 5 to 18 ring atoms - or more is selected as the (tetra) Na's miscellaneous dinosaur, in the beginning _ 4 ·, t , eg): "Base, (4) Atom. Heterocyclic aryl represents (eg, taro, quinoxalinyl, quinolinyl, isoquinolinyl, 128031.doc 200836742), benzophenanyl, benzocytyl, benzophenanthine , benzo, thiol, cryptyl, thiol, thioxyl fluorenyl, iso-Ml, tridecyl, tetradecyl, fluorenyl, yl, D-septyl D, benzoyl Heterocyclic aryl groups also include such substituted groups. Saturated or unsaturated 4, 5, 6 or 7 membered rings are cycloalkyl or heterocycloalkyl (common via ring A and ring B) j adjacent to two adjacent primary 2 bonds). A cycloalkyl group means a cyclic hydrocarbon having 3 to 7 ring atoms, preferably 3 to 6 ring atoms. The cycloalkyl group means, for example, a cyclopropyl group. Cyclobutyl, cyclopentyl or cyclo =. The cycloalkyl group may be optionally substituted. Heterocycloalkyl means that it may be saturated or unsaturated and contains one or more, preferably 1 to 3, selected from hydrazine, N. a monocyclic, bicyclic or tricyclic hydrocarbon of a hetero atom of *s. Preferably, it contains between 3 and 7 ring atoms. The term heterocycloalkyl also includes a bridged heterocycloalkyl group such as a hydroxy group. _8_Aza-bicyclo[3.2 oct-8-yl. ' "Saturation" in the context of ring B means at least not participating in a fusion bond with 3 (which is a bond between the ring atoms of ring A and ring B which may have an unsaturated or saturated bond). The atomic system is bonded to each other by a single bond. The ruthenium, _A-B (and thus R) has a different from the unsubstituted benzothiazolyl group from the above or below and is different from the unsubstituted benzo[b] a fused ring group of the thienyl group, but may include a substituted benzothiazolyl group or a substituted benzo[b]thienyl group, especially a heart a7 alkoxy-benzothiazolidine The base 'such as 6-methoxy-benzoindole-2-yl. Most preferably, the -Α-fluorene is selected from the group consisting of dihydrobenzo-128031.doc 200836742 dioxane Dilute H oxacyclopentenyl and dihydrobenzopyrene. South base, or selected from benzodioxanyl, indanyl, unsubstituted or c "C7 alkyl substituted 2H_ Benzo[]L,4]oxazinyl, unsubstituted or at most (^-(:7 alkyl substituted 4,5,6,7,8-tetrahydronaphthyl and alkoxy substituted benzene) And a sulfhydryl group, more preferably selected from 2,3-dinitrogen.Benzene is called dioxane- a 6-yl, benzodioxol-5, a 2,3-dihydro-benzofuran-5-yl and a 2,3-dihydro-benzofuranyl group, or a benzo[丨^]dioxine-6-yl, benzofuranyl, indoline _5-yl, carboxymethyl·3, dihydrogen-2H_benzo[1,4]oxazine-7 _ base, anal methyl _3,4_ dihydro 2 hydrazine benzene [MP oxazine · 6-yl, 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro _ Naphthalene-2-yl and 6-methoxy-benzothiazol-2-yl. ''Condensed' preferably means that the ring system shares 2 ring atoms and one (saturated or unsaturated) bond. The salt which can be attached to a salt includes an acid addition salt formed with a conventional acid, for example, an inorganic acid such as hydrochloric acid or sulfuric acid (tetra) acid; or an organic acid such as an aliphatic or aromatic carboxylic acid or sulfonic acid, for example Acetic acid, trifluoroacetic acid, propionic acid, butyl succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxy maleic acid, acetone oxime, double By acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, p-aminobenzenesulfonic acid or cyclohexylaminesulfonic acid; also an amino acid such as arginine and lysine. For a compound of the invention having 2 an acidic group such as a free carboxyl group, the pharmaceutically acceptable salt also means a metal salt or an ammonium salt such as an alkali metal salt or an alkaline earth metal barium such as a sodium salt, a potassium salt or a magnesium salt. a salt or a calcium salt, and an ammonium salt formed with ammonia or a suitable organic amine. 128031.doc 200836742 The agent of the present invention comprising a free hydroxyl group of the present invention may also be present in the form of a pharmaceutically acceptable, physiologically decomposable vinegar, and is also included in the scope of the present invention. Preferably, the pharmaceutically acceptable ester is a prodrug vinegar derivative which can be converted, under physiological conditions, by solvolysis or decomposition to contain the free agent of the present invention. Suitable for pharmaceutically acceptable prodrugs of vinegar, vinegar derived from a few acids, monoacetic acid or carboxylic acid, advantageously an ester which is substituted with a lower alkanoic or aryl carboxylic acid. Preferred compounds of formula (1) are: (2,3-dihydrobenzopyrene, 4]dioxanylene-isopropyl-phenyl)-6-propargyloxy-quinazoline_2 Methyl ketone; Benzo[1,3]dioxol-5-ylindole isopropyl-phenyl)-6-propargyloxy-quinazolin-2-yl]-methanone (2,3-Dihydro-benzofuran-5-yl)-[4-(4-isopropyl-phenyl)-6-propargyloxy-quinazolin-2-yl]-fluorenone. The invention also relates to a U-form I compound selected from the group consisting of benzo[1,4]dioxine-6-yl-[4-(4-isopropyl-benzene) (6-propargyloxy-quinazolin-2-yl]-fluorenone; a mouse known *"5-yl-[4-(4-isopropyl-phenyl)_6-propargyl Baseoxy-oxime.琳琳_2_ "基]-曱酉同; (2,3-Dihydro-benzofuranyl)-[4-(4-isopropyl-phenyl)-6-propargyloxy-quin Oxazolin-2-yl]-methanone; [4-(4-isopropyl-phenyl)-6-propargyloxy-indolyl]-(4-indolyl-3,4-di Hydrogen-2H-benzo[1,4]oxazin-7-yl)-methanone; •10-128031.doc 200836742 Benzofuran_5_yl-[4_(4-isopropyl-phenyl)_6 _propargyloxy-quinazoline-2-yl]-methanone; [4-(4-isopropyl-phenyl)_6-propargyloxy-quinazoline-2-yl]_(5 ,5,8,8 tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-methylate; *[4_(4-isopropyl-phenyl)·6·propargyl Hydroxy-quinazolin-2-yl]-(4-mercapto-3 • 3,4-dihydroindole-benzo[1,4]oxazin-6-yl ketone; and [4-( 4-isopropyl-phenyl)_6-propargyloxyquinazoline-2-yl]-(6-methoxy r., benzyl-benzothiazol-2-yl)-methanone; Or an individual pharmaceutically acceptable salt thereof According to a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient, diluent or carrier. The third aspect of the present invention provides a species for promoting Compounds of formula (1) that release thyroid hormones. It has been well established that patients treated with parathyroid hormone (PTH) and its analogues and ribs have significant assimilation effects on bone formation. Therefore, compounds that promote $PTH release, such as The compounds of the present invention are useful for the prevention or treatment of bone disorders associated with higher calcium depletion or resorption or for stimulating calcium fixation in the shape of bone. Thus, in a fourth aspect, the invention includes a method for prevention Or treating a method in which the girl is highly trained or re-absorbed or needs to stimulate the formation of bone and the bone condition fixed by the mother in the bone, and the towel is administered to a patient in need of the treatment as defined above (1) a compound, or a pharmaceutically acceptable and decomposable substance thereof, or an acid addition salt. In the fifth aspect, the invention provides a form for the preparation of the salt form in the free form or 128031.doc -11 - 200836742 A method of a compound of formula (I), which comprises the steps of oxidizing a compound of formula Ila:

Any standard oxidation procedure can be used, such as the use of Jones reagent under appropriate reaction conditions. The compound of formula IIa is conveniently prepared by reacting a compound of formula II with a suitable organometallic reagent such as a Grignard reagent under anhydrous conditions, as illustrated below:

Line Νγ^〇

Straw is made by any suitable route

The compound of formula II can be β, prepared, for example, as follows

12803 l.doc > 12- 200836742

The aniline of formula IV can be prepared by any convenient route, for example as described in WO 2002102782:

AcOH 20h.il

Other starting materials are commercially available, can be synthesized according to methods known in the art, and/or can be prepared by methods described in the Examples or analogous to those described in the Examples. 128031.doc -13- 200836742 Swim away > The compound of formula (i) can be converted to the salt form in a conventional manner and vice versa. The compounds of the invention can be recovered from the reaction mixture and purified in a conventional manner. Isomers such as enantiomers can be obtained in a conventional manner, for example, by fractional crystallization or asymmetric synthesis from the corresponding asymmetrically substituted (e.g., optically active) starting materials. In a sixth aspect, the invention includes the use of a compound of formula (1) for the manufacture of a bone condition for the prevention or treatment of calcium depletion or resorption associated with or requiring stimulation of bone formation and calcium fixation in bone Used medicine. In a seventh aspect, the invention provides a combination for simultaneous, individual or sequential treatment comprising a therapeutically effective amount of a compound as described above and a second pharmaceutical substance selected from the group consisting of calcium and calcitonin Or an analogue or derivative thereof, a steroid hormone, a partial estrogen agonist or an estrogen-progestin combination, a SERM (selective estrogen receptor modulator), a vitamin d or an analogue thereof or a PTH, PTH fragment or PTH derivative. [Embodiment] The agent of the present invention can be prepared by the method described below as a non-limiting example: Analytical HPLC conditions are as follows: Apparatus and setting: Agilent 110 System with G1311A four-stage pump (0.8 ml volume) , G1313A autosampler 〇μ1 injection volume), G1316A column compartment (35 ° C), G1315A diode array detector (by UV absorption detection at 210 nm-25 0 nm wavelength), APC ionization 128031.doc -14- 200836742 G1946A mass spectrometer. Columns · Waters Symmetry C8, 50 X 2.1 mm, 3.5 μιη average particle size. Flow rate ΐ·〇 ml/min. Linear gradient: 5% of A in 2 · 0 min B to 95% of A in B. A: water containing 5% acetonitrile and 0.1% TF A; B: acetonitrile containing 0.1% TFA. Example 1: (2,3-Dihydro-benzo[1,4]dioxine-6-yl)-[4-(4-isopropyl-phenyl)-6-propyloxy -喧嗤琳-2-yl]-methanone

At 130 mg (0.28 mmol) (2,3-dihydro-benzo[M]dioxine-6-yl)-[4-(4-isopropyl-phenyl)-6-propyl 126 _.33 眶〇 1) 2.61 ^ Jones reagent was added dropwise to a solution of oxy hydrazine in a solution of 5 ml of acetone. The mixture was darkened and stirred at room temperature for 15 minutes to complete the reaction. After concentration under vacuum (i.V.), the residue was partitioned between ethyl acetate and water/carbonic acid. The organic phase was dried over anhydrous magnesium The product was obtained as a pale yellow solid. • H-NMR (400 MHz, CDC13): 8.17 (d5 1Η), 7.83 (d, 2Η)> 7.73 (d,1Η), 7.71 (dd,1Η), 7.64-7.69 (m,2Η), 7.42 ( d,2Η) 128031 .doc λ r 200836742 6.93 (d? 1H)? 4.79 (d? 2H), 3.02 (seven peak, lpi) MS: 465 (M+i)+ Preparation of starting material: 4.31-4.35 ( m? 2H)5 4.26-4.30 • 62 (t, 1H), 1.32 (d, 6H). (m,

A) 4 (4 〆, propyl-phenyl) {bromopropyloxy 喧嗤 喧嗤 甲酸 甲酸 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 7 ml of water and 1.4 g (6·8 mmol) of ethyl glyoxylate (5 % by weight in toluene) were added to a mixture of 4 - isopropyl-phenyl) fluorenone and 16 g of ammonium acetate. In the air

After vigorous stirring for 3 days in the presence of gas, the reaction mixture was extracted with water and ch2C12. The organic layer was dried over MgSO 4 and evaporated. Purification by flash chromatography (hexane/ethyl acetate) afforded ethyl 4-(4-isopropyl-phenyl)-6-propyipropyloxy-quinazoline-2-carboxylate. ^-NMR (300 MHz, CDC13): 8.30 (d5 1H)? 7.83 (d, 2H)? 7.67 (dd, 1H), 7·65 (s5 1H), 7.43 (d, 2H), 4.79 (d, 2H) ), 4.60 (q, 2H), 3.04 (seven peak, 1H), 2.61 (t, 1H), 1.50 (t, 3H), 1.34 (d, 6H) MS: 375 (M+l) + 128031.doc - 16 - 200836742 B) [4-(4-Isopropyl-phenyl)_6-propargyloxy-quinazoline-2-yl]] methanol was cooled in water/ice bath 1.0 g (2.67 mmol) 4· Ethyl (4-isopropyl-phenyl)-6-propargyloxy-quinazoline-2-carboxylate was dissolved in 2 〇ml of thf* and treated with 1·6 ml of 1 Μ lithium aluminum hydride. After the completion of the addition, the reaction was terminated by pouring the reaction mixture into a saturated ammonium chloride/ethyl acetate solution. Extraction and vacuum concentration gave the product as a yellow oil. The crude material was used directly in the oxidation step below. C) 4-(4-Isopropyl-phenylpropargyloxy-quinazoline-2-formaldehyde oxidized 3.9 g (11.7) with 1 · 1 equivalent of Dess-Martin reagent at room temperature Ment) a solution of the alcohol prepared in the step in 4 ml of dichloromethane. After stirring for 3 h, the mixture was filtered and distributed between ethyl acetate, water and sodium thiosulfate solution, and the organic phase was concentrated. Crude aldehyde, which was purified by recrystallization from a mixture of ethyl acetate / hexanes to give a yellow brown solid. H-NMR (400 MHz, CDC13): 10.29 (s, 1H), 8.25 (d, 1H) ), 7·82 (d, 2H), 7.67-7.72 (m, 2H), 7.45 (d, 2H), 4.80 (d, 2H), 3.04 (seven peak, 1H), 2.62 (t, 1H), 1.33 (d,6H) D) (2,3-Dihydro-benzo[1,4]dioxine_6_yl)-[4_(4-isopropyl-phenyl)-6-yne Propyloxy-quinazoline_2-yl]-methanol was used to treat 48 mg (2.0 mmol) of 6 mg (2.0 mmol) 6-bromo-1,4-benzodiazepine as a solution in 2 ml of THF. A suspension of the chips in 2 ml of THF. The reaction mixture was stirred at 60 ° C for an additional 20 minutes, cooled to room temperature and then added to 495 mg (1.5 mmol) of 4-(4-isopropyl-phenyl)-6-br. Base-喧 淋 -2--2-A disk (in 6 ml of THF) 128031.doc -17- 200836742 in the cold solution (5 C). After the addition was completed, stirring was continued for 1 hour at room temperature. The mixture was poured into 2 mL of saturated ammonium sulfate solution and extracted with ethyl acetate. The crude material was purified by silica gel chromatography (di-methane/methanol) to afford alcohol as a pale yellow solid. W-NMR (400 MHz, CDC13): 8.02 (d, 1H), 7.73 (d, 2H), 7.56-7.61 (m5 2H)5 7.41 (d? 2H)? 7.06-7.11 (m3 2H)5 6.81 (d , 1H), 5.94 (d, 1H), 5·15 (d, 1H), 4.73 (d, 2H), 4.21 (s, 4H), 3.03 (seven peak, 1H), 2.58 (t, 1H), 1.33 (d, 6H) o MS: 467 (M+l)+ Compounds of the following examples were prepared in a similar manner using the appropriate starting materials: Example 2. Pupid [1,3]dioxol-5-yl _[4_(4_isopropyl_phenyl)_ 6-propargyloxy-quinazoline-2-yl]-methanone

H-NMR (400 MHz, CDC13): 8.17 (d5 1H)? 7.83 (d? 2H)? 7·76 (dd, 1H), 7.65-7.69 (m, 3H), 7.42 (d, 2H), 6 · 87 (d, 1H), 6.06 (s, 2H), 4·79 (d, 2H), 3.02 (seven peak, 1H), 2.62 (t, 1H), 1.32 (d, 6H). MS: 451 (M+l) + Example 3: (2,3-dihydrobenzofuran-5-yl)-[4-cyclohexyl-phenyl-phenyl]_6_128031.doc -18- 200836742 propargyl Oxy-indolyl-2-yl]-methanone

W-NMR (400 MHz, CDC13): 8.17 (d, 1H), 8.05 (s, 1H), 7.99 (d, 1H), 7·83 (d, 2H), 7·63-7·69 (m, 2H), 7.42 (d, 2H), 6.81 (d, 1H), 4.79 (d, 2H), 4.67 (t, 2H), 3.26 (t, 2H), 3.02 (seven peak, 1H), 2.62 (wide peak) , t, 1H), 1.32 (d, 6H). MS: 449 (M+l) + Example 4: benzo[1,4]dioxan-6-yl-[4-(4-isopropyl-phenyl)-6-propanyloxy Base-quinoline-2-yl]-hypothyroid

!H-NMR (400 MHz, CDC13): 8.15-8.19 (m5 1H)5 7.82 (td, 2H), 7.64-7.73 (m, 3H), 7.49 (d, 1H), 7.43 (d, 2H), 6.68 (d, 1H), 5.90 (m, 2H), 4.79 (d, 2H), 3.03 (seven peak, 1H), 2.62 (t, 1H), 1.33 (d, 6H). 128031.doc -19- 200836742 MS: 463 (M+l)+ 6-bromo-benzo[i,4]dioxine for use in the Grenner reaction according to the literature procedure (C· Kashima, A Tomolake, J. Org. Chem. 1987, 52, 5616). Example 5: Indoline-5-yl-[4-(4-isopropyl-phenyl)-6-propargyloxyquinoxaline-2-yl]-methanone

b-NMR (400 MHz, CDC13): 8.18 (d, 1H), 7.98 (s, 1H), 7.92 (d, 1H), 7.83 (d, 2H), 7·64_7·70 (m, 2H) , 7.42 (d, 2H), 7.31 (d, 1H), 4.79 (d, 2H), 2.92-3.07 (m, 5H), 2.62 (t, 1H), 2·12 (five peaks, 2H), 1.32 (d, 6H). MS: 447 (M+l) + Example 6: (2,3-dihydrobenzofuran-6-yl)-[4-(4-isopropyl-phenyl)-6-propargyloxy - quinazoline_2_yl]-methanone

128031.doc -20- 200836742 old), 7.83 (d, 2H), old), 7.42 (d, 2H), 1H-NMR (400 ΜΗζ, CDC13)·· 8.17 (d5 7.68 (td, 2H), 7· 65 (d,1H), 7.55 (d, 2H), 3.28 (t? 2H)3 le32 (d,6H). MS: 7.29 (d,1H), 4.79 (d,2H),4·63 (t5 3_02 (Seven heavy peak, 1H), 2.62 (t, 1H), 449 (M+l) + Example 7: [4-(4-isopropyl-phenyl)_6-propargyloxyquinazoline] _ (4-mercapto-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)- formazan

ϋ b-NMR (400 MHz, CDC13): 8.16 (d, 1H), 7.83 (d, 2H), 7.73 (dd, 1H), 7.61-7.67 (m, 2H), 7·58 (d5 1H), 7.41 (d, 2H), 6.63 (d, 1H), 4.78 (d, 2H), 4.24 (wide peak, t, 2H), 3·42 (wide peak, t, 2H), 3·01 (m, 4H) , 2.61 (t, 1H), 1.32 (d, 6H). MS: 478 (M+l) + Example 8 ··Benzylpyranyl-[4-(4-isopropyl-phenyl)-6-propargyloxy-quinazolin-2-yl]-曱 ketone 128031.doc -21 - 200836742

h-NMR (400 MHz, CDC13): 8.44 (s, 1H), 8.18 (t, 2H), 7.85 (d, 2H), 7.65-7.72 (m, 3H), 7.58 (d, 1H), 7.42 (d) , 2H), 6.84 (wide peak, s, 1H), 4.80 (d, 2H), 4.24 (wide peak, t, 2H), 3.02 (m, 1H), 2_62 (t5 1H), 1.32 (d, 6H) . MS: 447 (M+l) + Example 9: |; 4_(4-isopropyl-phenyl)-6-propargyloxy-quinazolin-2-yl]-(5,5,8, 8-tetradecyl-5,6,7,8-tetrahydro-cai-2-yl)-fluorenone

^-NMR (400 MHz5 CDC13): 8.16-8.21 (m? 2H)? 7.81-7·87 (m, 3H), 7.64-7.70 (m, 2H), 7·37-7·44 (m, 3H) , 4·80 (d, 2H), 3.02 (seven peak, 1H), 2.61 (t, 1H), 1.71 (s, 4H), 1.32 (d, 6H), 1.30 (s·6H), 1.29 (s, 6H), MS: 517 (M+l) + 128031.doc -22- 200836742 Example 10: [4-(4-Isopropyl-phenyl)-6-propargyloxy-quinazoline-2- ]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-anthone

iH-NMR (400 MHz, CDC13): 8_17 (d, 1H), 7.83 (d, 2H), 7.61-7.69 (m, 2H), 7.58-7.61 (m, 1H), 7.41 (d, 2H), 7.35 -7.41 (m,1H), 6.77 (d,1H), 4.79 (d,2H), 4.37 (t, 2H),3·28 (t,2H), 3.02 (seven peak, 1H), 2.94 (s, 3H), 2.61 (wide peak, t, 1H), 1.32 (d, 6H). MS: 478 (M+l) + EMI17.1: [4-(4-isopropyl-phenyl)-6-propargyloxy-quinazolin-2-yl]-(6-methoxy- Benzothiazol-2-yl)-methanone

A solution of 400 mg (1.64 mmol) of 2-bromo-6-methoxy-benzothiazole in 2 ml of 10% dioxane in THF was cooled to -75 ° C under argon atmosphere and used with 128031. -23 - 200836742 1.6 ml (1.76 mmol) of a solution of a second butyl lithium lithium chloride complex (1 j M in THF; Chemetall, Frankfurt). After stirring the resulting mixture for a few minutes at low temperature, 350 mg (1.06 mmol) of 4-(4-isopropyl-phenyl)-6-propargyloxy-quinoline was added dropwise at _75 °C. Lin_2_A (Comparative Example 1C) solution in 5 ml of THF. Continue mixing for 5 hours at the same temperature. This was partitioned between water and ethyl acetate, followed by chromatography (hexane/ethyl acetate) to give the s. 1h, NMR (400 MHz, CDC13): 8.30 (d, 1H), 8.17 (d, 1H), 7·90 (d, 2H), 7.68-7.74 (m, 2H), 7.47 (d, 2H), 7 · 42 (d, 1H), 7.18 (dd, 1H), 4.81 (d, 2H), 3.93 (s, 3H), 3.05 (seven peak, 1H), 2.63 (t, 1H), 1·35 (d, 6H). MS: 494 (M+l) + starting material 2-bromo-6-methoxy-benzothiazole according to the literature procedure (N.

Suzuki et al., Chemistry Express 1992, 7, 717) were prepared by using the commercially available 2-amino-6-methoxy-benzothiazole PEG to assist the Sandmeyer reaction. Example 12 · 3-[4-(4-Isopropyl-phenyl)-6-propargyloxy-oxime.坐琳_2-carbonyl]-苐-9-酉同 A.Synthesis of 2-bromo--9-one

Br treated with 1·5 ml (1.2 mmol) of tetrabutylammonium hydroxide (in MeOH solution) 15.0 g (61.2 mm 〇l) 2 bromo- hydrazine at 65 mln ratio bite 128031.doc -24- Solution in 200836742. Air was bubbled through the mixture for 6 hours. The yellow solid formed was dissolved in ethyl acetate and extracted with water. Recrystallization from ethyl hydrazine yielded the pure title product. !H-NMR (400 MHz3 CDC13): 7.76 (d3 1H), 7.66 (dd5 1H), 7.61 (dd, 1H), 7·49-7·52 (m, 2H), 7.39 (wide, d, 1H) ), 7.30-7.35 (m,1H) 〇B. 2-bromo-9-trimethyldecyloxy-9H-indole-9-carbonitrile

Hey.

The ketone obtained in Step A (2·59 g; 1〇·〇 mm〇i) was dissolved in 15 ml of acetonitrile and treated with a catalytic amount (185 mg; 2.0 mmol) of fluorinated planer. A solution of 2.0 ml of trimethylsulfonyl cyanide (15.0 mmol) diluted with 5 ml of acetonitrile was added dropwise under an argon atmosphere. A yellow solution formed which slowly turned brown. After the addition of the thin layer chromatography showed the mixture was partitioned between water and ethyl acetate, washed with brine and concentrated in vacuo. The resulting brown solid was used without further purification. b-NMR (400 MHz, CDC13): 7.85 (s, 1H), 7.72 (d, 1H), 7.61 (t, 2H), 7.45-7.53 (m, 2H), 7.41 (t, 1 Η), 0·14 (s,9H) 〇C· 3-{radio-[4-(4-isopropyl-phenyl)-6-cropropyloxy-quinalin-2-yl]-methyltrimethyl矽alkyloxy-9H-苐-9-carbonitrile 128031.doc -25- 200836742 }(

The bromide prepared in step B (358 mg; 1.00 mmol) was dissolved in 3 ml of THF, cooled to -15 ° C and isopropylidene solution was gasified with 0.91 ml (1. 〇〇mm〇l). Chemetall; treated with 1 · 1 Μ solution in THF). Stirring was continued overnight while warming to room temperature. After cooling to -8 〇t, add 317 mg (l. 〇〇mm〇i) 4-(4-isopropyl-phenyl)_6 propargyloxy-quinazoline-2-carbaldehyde (step lc ) a solution in 3 ml of THF. The desired secondary alcohol is formed within a few minutes after the addition is completed. The mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. Purification by flash chromatography (ethyl acetate / hexanes) gave product as a viscous yellow solid. D· 3-{hydroxy·[4·(4-isopropyl-phenyl)-propargyloxy-quinazoline_2·yl]·methylhydrazine-9-one 128031.doc -26 - 200836742

The product of Step C above (115 mg; 〇·1 89 mmol) was dissolved in 5 ml of THF and treated with 250 mg (0.38 mmol) of tetrabutylammonium fluoride absorbed on silica gel (15 mmol/g). . The reaction was completed after stirring for 2 hours. The mixture was filtered and the filtrate was dissolved in a water/ethyl acetate mixture. The organic layer was separated, washed with brine and concentrated vacuum. Flash chromatography (hexane/ethyl acetate) gave the product as a yellow solid. iH-NMR (400 MHz, CDC13): 8.04 (d, 1H), 7.89 (s, 1H), 7.81 (d, 1H), 7.72 (dd, 2H), 7.62 (s, 1H), 7.59 (d, 2H) ), 7.48 (d, 2H), 7.45 (d, 1H), 7.41 (d, 2H), 7.22-7.28 (m5 1H, below CHC13 signal), 6.04 (d, 1H), 5.39 (d, 1H) , 4.74 (wide peak, s, 2H), 3.02 (seven peak, 1H), 2.56-2.59 (m, 1H), 1.33 (d, 6H). MS: 511 (M+l) + E. 3-[4-(4-isopropyl-phenyl)-6-propargyloxy-quinazoline-2-carbonyl-purin-9-one 128031. Doc -27- 200836742

The alcohol prepared in Step D was oxidized with a Jones reagent as described in Example 1 to give the title compound of Example 12. ^-NMR (400 MHz, CDC13): 8.44 (dd5 1H)5 8.42 (s, 1H), 8.20 (d, 1H), 7.85 (d, 2H), 7.61-7.75 (m, 4H), 7.65 (d, 1H), 7.56 (t, 1H), 7.43 (d, 2H), 7.39 (t, 1H), 4.81 (d, 2H), 3.03 (seven peak, 1H), 2.63 (t, 1H), 1·32 ( d, 6H). MS: 509 (M+l) + Example 12: Inhibition of intracellular calcium transients stimulated by extracellular calcium: In the test system described in detail below, the following ranges of ICso values were found: Example compound IC50 (nm) (compound) Within the range of 2, 3, 6, 7, 8, 12 0_2 to less than 0.5 1,4,5 0.5 to less than 19, 10 1 to less than 5 11 5 to 10 in free form or pharmaceutically acceptable An agent of the invention as defined above in the form of an acid addition salt, such as an agent of formula (I), especially as exemplified, exhibits pharmacological activity and is suitable for use as, for example, a medicament for therapy, It is used as a medicine for the treatment of diseases and conditions as described below. 128031.doc -28· 200836742 Intracellular Free Calcium Assay: A method for determining antagonism at PcaR involves measuring inhibition of intracellular calcium transients by extracellular calcium. CCL39 fibroblasts stably transfected with human PcaR were seeded at 40,000 - cells/well into a 96-well viewplate and cultured for 24 hours. The medium was then removed and replaced with fresh medium containing 2 μΜ Fluo_3 AM (Molecular Probes, Leiden, The Netherlands). In the experiment, the cells were cultured for 1 h at 37 ° C, 5% CO 2 . Thereafter, the plate was washed twice with mHBS and refilled with 丨〇〇 μ1 mHBS containing the test compound. Incubation was continued for 15 minutes at room temperature. To record changes in intracellular free calcium, the plates were transferred to a fluorescence imaging plate reader (Molecular Devices, Sunnyvale, CA, USA). The record contains a baseline of 5 measurements (camera excitation 488 nm) each for 4 seconds. Subsequently, the cells were stimulated with calcium (final 2.5 mM) and the fluorescence changes were recorded for 3 minutes. When measured in the above assay, the agent of the invention typically has about

^ 丨 Erasing to IC5() in the range of about 1 sec or less, preferably in the range of G.2 nM to 10 nM. It has been well established that patients treated with parathyroid hormone (PTH) and its analogues and tablets have significant assimilation effects on bone formation. Thus, a compound that promotes PTH release, such as an agent of the present invention, can be used to prevent or treat a bone condition associated with higher calcium depletion or resorption or that requires stimulation of bone formation and calcium fixation in bone. Because: in another aspect, the invention includes a method for preventing or treating or associated with the depletion or resorption of sputum or the need to stimulate bone formation and bone. 128031.doc -29-200836742 The treated patient is administered a therapeutically effective amount of the agent of the invention having a calcium-fixed bone condition. In yet another aspect, the invention includes a pharmaceutical combination for preventing or treating a disease associated with greater consumption or resorption, and stimulating the formation of bone and the monthly condition of calcium in the bone. Hair /, G 3 This kind of music and medicine can be connected to the X (four) agent, thinner or _ mixture. Therefore, the agent of the present invention is used for preventing or treating all of the bones of the bones, which are associated with resorption or which are required to stimulate the formation of bones and the calcium fixation in the bone, or the joints of the bones due to the joints. Acute or chronic morbidity associated with bone loss caused by inflammation or osteoarthritis, or for the treatment of parathyroid dysfunction. Symptoms such as osteoporosis, rupture, bone disease, including bone demineralization, of various origins (eg, adolescent, menopausal, postmenopausal, post-traumatic 'caused by ageing or by corticosteroid therapy or inactivity) Other diseases and conditions that can be prevented or treated include, for example, seizures, strokes, head trauma, spinal cord injuries, hypoxia-induced neuronal damage such as in cardiac arrest or neonatal distress, epilepsy, such as Azhai Alzheimer's disease, Huntingt〇n, s disease, and Parkinson's disease, neurodegenerative diseases, dementia' muscle tension, depression, anxiety, panic disorder , obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, antipsychotic malignant syndrome, congestive heart failure; hypertension; visceral motor disorders such as diarrhea and colon fistula and dermatological disorders such as in tissue healing Such as burns, ulcers and wounds. 128031.doc -30- 200836742 In particular, the agent of the present invention is shown to be loose. ',; Prevention or treatment of bone of various origins For all of the above uses, the amount of juice is not more than 0.03 mg to 3, 00 mg, preferably 〇〇 3 mg to 30 mg, more preferably 0.1. From mg to 10 mg of the compound of the formula. Ben Shi Xi - + July can be administered twice a day or twice a week. The agent of the present invention can be administered in the form of a formula, or a pharmaceutically acceptable salt form f. These salts are conventionally prepared in a white manner and exhibit the same level of activity as the free compound. The present invention provides a pharmaceutical composition comprising a pharmaceutical agent of the present invention in the form of a free base or in the form of a freely acceptable salt in the form of a free base, and a pharmaceutically acceptable Susanna丨 十# ^ ^, Dilution or Carrier. These compositions can be formulated in a conventional manner. The medicine of the present invention is also known as Liang Zhi! The sperm is administered by any conventional route, "if not, 'di-intestinal fistula', for example, in the form of an injectable solution, microemulsion or suspension; enterally administered, eg, orally, for example, In the form of a troche or capsule, or administered as a transdermal, nasal or suppository. According to another embodiment of the invention, the agent of the invention may be used as an adjuvant to potting therapy or _ 'these other therapies such as use (4) Resorption of therapies for inhibition of d such as osteoporosis therapy, especially for the treatment of calcium, calcitonin or its analogues or derivatives (such as sputum, sputum or human calcitonin), steroid hormones (eg Estrogen or a combination of hormone-progestin, SERM (selective hormone receptors) (eg raloxifene, rasopoxifene, benzoxene) Bazed〇xifene), arz〇xifene, fc1271, tibolone (Tib〇l〇ne) (Liviai8, RANKL antibody (eg, denosumab 128031.doc -31 - 200836742 (denosumab)), a cathepsin inhibitor, vitamin bismuth or an analogue thereof or PTH, PTH fragment or PTH derivative Q, JWPTH (1-84), PTH (1-34), ΡΤΗ (1-36), ΡΤΗ (1-38), PTH (1-31) NH2 or PTS 893).

When the agent of the present invention is administered together with bone resorption inhibition therapy, for example, as an adjuvant for bone resorption inhibition therapy, the agent S for co-administering the inhibitor will of course depend on the type of inhibitor drug used (eg, Whether it is steroid or calcitonin depends on the condition to be treated, whether it is curative or preventive therapy, depending on the protocol. According to the above, the present invention further provides a pharmaceutical agent of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament; b) a medicament for preventing or treating the above-mentioned disorder in an individual in need of such treatment and The method of treating a method comprising administering to the individual an effective amount of an agent of the invention or a pharmaceutically acceptable salt thereof; c) a medicament suitable for the preparation of, for example, a method as described in b) above Composition of the present invention or a pharmaceutically acceptable salt thereof 1 w According to another embodiment of the present invention, the agent of the present invention can be used as other adjuvants or other adjuvants such as (4) Respiratory inhibitor therapy, such as osteoporosis therapy, especially for the use of: (4), (4) its analogues or derivatives (such as shoes, serotonin), steroid hormones (such as estrogen), Partial estrogen stimulating effect; diterpene-progestin combination, SERM (selective estrogen receptor modulation = 1 = nooxib laxoxifene, TSE_424, bupreb), vitamin D or its analogues Or ΡΤΗ, ρτΗ fragment or 128031.doc • 32 * 200836742 PTH derivatives (eg PTH (l-84), PTH (l-34), PTH (i_36), ΡΤΗ (1-38), PTH (1-31) NH2*PTS 893). When the agent of the present invention is administered together with a bone resorption inhibition therapy, for example, as an adjuvant for bone resorption inhibition therapy, the dose of the co-administered inhibitor will of course depend on the type of inhibitor drug used (eg, Whether it is for steroids or activitis, depending on whether you want to treat it or preventive therapy, depending on whether it is 4

128031.doc -33 -

Claims (1)

200836742 X. Patent application scope: !•-Formula (1) compound or its pharmaceutically acceptable salt (I) wherein - the silk has a group having two fused rings -AB, wherein A is optionally substituted with a heteroaryl or aryl group and B is optionally a sleeve, West A ^, &lt; a saturated or unsaturated 4, 5, 6 or 7 membered ring of a hetero atom of 〇, Ν and S; an optional substituent on R is one or more independently selected from the group below a group: a pendant oxy group, a cyano group, a halogen group or other optionally substituted C2-C6 fluorenyl group, a Ci-C6 alkoxy group, an amine group; the other optional substituents are selected from the group consisting of a cyano group and a dentate group. , Cl-c6 alkyl, Cl-c6 alkenyl, Cl_c6 alkoxy, amine. 2. The compound of claim 1 wherein A is phenyl. 3. A compound according to claim 1 or 2 wherein B is a 5-membered ring. 4. A compound according to claim 1 or 2 wherein A is phenyl and B is fused at the 3' position and position of the phenyl group. 5. A compound of claim 1 or 2 wherein B contains 2 oxygen groups, each of which is directly bonded to the heteroaryl or aryl ring. 6. The formula of claim 1 [compound wherein R is selected from the group consisting of dihydrobenzodioxium 128031.doc 200836742 7. 8. Οcyclohexenyl, benzodiazepine pharmaceutically acceptable And a compound of the formula 1 wherein the R is selected from the group consisting of benzodioxan, sulphate, unsubstituted or fluorene. ^7 alkyl substituted 211_benzo[1, oxazinyl, unsubstituted or at most substituted by Ci_c 4, 5, 6,7,8-tetrahydronaphthyl and substituted with 7 silk Sputum, or a pharmaceutically acceptable salt thereof. A compound according to claim 1 or 2 which is selected from the group consisting of: (2'3-monophos-benzo[1,4]dioxan-6-yl)-[4-(4-iso) Propyl-phenyl)-6-propargyloxy-quinazoline-2-yl]-methanone; benzo[1,3]dioxolyl-[4-(4-isopropyl -Phenyl)-6-propargyloxyquinazolin-2-yl; μmethanone; (2,3-monohydro-benzofuran_5-yl)·[4_(4_isopropyl Base-phenyl)-6-propargyloxy-quinazolin-2-yl]-methanone. 9. A compound of formula I as claimed in claim 1, which is selected from the group consisting of the following compounds: benzo[1,4]dioxine_6_yl_[4_(4_iso) Propyl-phenyl)_6-propargyloxy-hydrazin-2-yl]-methanone; indoline-5-yl-[4-(4-isopropyl-phenyl)-6- Propargyloxy-quinazolin-2-yl]-anthracene; (2,-hydro-benzoquinone-snap-6-yl)-[4-(4-isopropyl-phenyl)-6 -propargyloxy-σ sit 4 wood-2-yl]-carbamidine; [4-(4-isopropyl-phenyl)_6-propargyloxy-quinazolin-2-yl] -(4-methyl-3,4-nitroso-2H-benzoquinone [1,4] σ 唤-7-yl)-曱酉同; 128031.doc -2- 200836742 benzopyran-5- -[4-(4-isopropyl-phenyl)-6-p-propyloxymethan-2-yl]-methanone; [4-(4-isopropyl-phenyl)-6 Fast propyloxy quetiapine tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone; [4-(4-isopropyl-phenyl)-6- Propargyloxy_啥嗤琳_2, its signature &quot;J,(4_p base_3,4-dihydro-2Η-benzo[1,4]°嘹-6-yl)_甲@ Same; and [4_(4-isopropyl-phenyl)-6-propargyloxy-.奎^坐琳基基本本嗟°坐-2-基)-甲嗣; or its individual pharmaceutically acceptable salts. 10. A pharmaceutical composition comprising a compound of formula (1) and pharmaceutically. An excipient, diluent or carrier. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> A compound of formula (I), or a pharmaceutically acceptable salt thereof, as shown in claim 1, for promoting the release of parathyroid hormone. 12. A process for the preparation of a compound of formula (I) in a free form or in the form of a salt, such as #1, which comprises the step of oxidizing a &amp; compound using a suitable oxidizing agent: 13. Use of a compound of formula (I) for the prevention or treatment of a calcium deficiency or resorption associated with higher calcium depletion or resorption or for stimulating bone formation and bone. 128031.doc 200836742 Used medicine. 14. A combination for simultaneous, individual or continuous treatment comprising a compound according to any one of claims 1 to 8 and a first drug substance selected from the group consisting of calcium and calcium Or its analogue or derivative, steroid hormone, partial estrogen agonist or estrogen _progestin combination, SERM (selective estrogen receptor modulator), RANKL antibody, cathepsin # preparation, vitamin D or an analog thereof or a PTH, PTH fragment or PTH derivative. 128031.doc 200836742 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the representative figure is simple: f-: VIII. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 128031.doc -4-